Heterocyclic compounds

ABSTRACT

The invention concerns pharmaceutically useful compounds of the formula I, in which Q, X, G1, Z and Ra have the various meanings defined herein, and their non-toxic salts, and pharmaceutical compositions containing them. The novel compounds are of value in treating conditions such as hypertension and congestive heart failure. The invention further concerns processes for the manufacture of the novel compounds and the use of the compounds in medical treatment.

This invention concerns novel heterocyclic compounds and, moreparticularly, novel heterocyclic compounds which possesspharmacologically useful properties in antagonising at least in part oneor more of the actions of the substances known as angiotensins, and inparticular of that known as angiotensin II (hereinafter referred to as"AII"). The invention also concerns pharmaceutical compositions of thenovel compounds for use in treating diseases or medical conditions suchas hypertension, congestive heart failure and/or hyperaldosteronism inwarm-blooded animals (including man), as well as in other diseases ormedical conditions in which the renin-angiotensin-aldosterone systemplays a significant causative role. The invention also includesprocesses for the manufacture of the novel compounds and their use intreating one of the afore-mentioned diseases or medical conditions andfor the production of novel pharmaceuticals for use in such medicaltreatments.

The angiotensins are key mediators of the renin-angiotensin-aldosteronesystem, which is involved in the control of homeostasis andfluid/electrolyte balance in many warm-blooded animals, including man.The angiotensin known as AII is produced by the action of angiotensinconverting enzyme (ACE) on angiotensin I, itself produced by the actionof the enzyme renin on the blood plasma protein angiotensinogen. AII isa potent spasmogen especially in the vasculature and is known toincrease vascular resistance and blood pressure. In addition, theangiotensins are known to stimulate the release of aldosterone and henceresult in vascular congestion and hypertension via sodium and fluidretention mechanisms. Hitherto there have been a number of differentapproaches to pharmocological intervention in therenin-angiotensin-aldosterone system for therapeutic control of bloodpressure and/or fluid/electrolyte balance, including, for example,inhibiting the actions of renin or ACE. However, there remains acontinuing need for an alternative approach because of the side-effectsand/or idiosyncratic reactions associated with any particulartherapeutic approach.

In our published co-pending European Patent Applications, PublicationNos. 399731, 412848, 454831 and 453210 there are respectively disclosedcertain imidazopyridine, quinoline, naphthyridine and pyridinederivatives which have AII antagonist activity.

We have now discovered that the compounds of the invention (set outbelow) surprisingly antagonise one or more of the actions of thesubstances known as angiotensins (and in particular of AII) and thusminimise the physiological effects associated with their presence inwarm-blooded animals (including man) and this is the basis of theinvention.

According to the invention there is provided a heterocyclic compound ofthe formula I (set out hereinafter, together with the other chemicalformulae identified by Roman numerals) wherein Q is selected from agroup of the partial structural formula IIa, IIb, IIc or IId in which

ring B of formula IIa completes a benzene or pyridine ring;

R¹ and T¹ are independently selected from (1-8C)alkyl, (3-8C)cycloalkyl,(3-8C)cycloalkyl-(1-4C)alkyl, phenyl, phenyl(1-4C)alkyl or substituted(1-4C)alkyl, the latter containing one or more fluoro substituents orbearing an (1-4C)alkoxy substituent;

R² and T² are independently selected from hydrogen, (1-8C)alkyl,(3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-4C)alkyl, carboxy,(1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro, phenyl orphenyl(1-4C)alkyl;

R³ and R⁴ are optional substituents on ring B independently selectedfrom (1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano, nitro,fluoro(1-4C)alkoxy, hydroxy or hydroxy(1-4C)alkyl;

T³ is selected from halogeno, (1-4C)alkoxy, amino, alkylamino anddialkylamino of up to 6 carbon atoms and any of the values defined forT¹ ;

T⁴ is selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylcontaining one or more fluoro substituents, carboxy,(1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, halogeno, cyano, nitro,carbamoyl, (1-4C)alkanoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl ofup to 7 carbon atoms, amino, alkylamino and dialkylamino of up to 6carbon atoms, and a group of the formula -A¹.B¹ wherein A¹ is(1-6C)alkylene, a carbonyl group or a direct bond and B¹ is

(1) an unsubstituted phenyl or phenyl bearing one or two substituentsindependently selected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano,trifluoromethyl, nitro, hydroxy, carboxy, (1-4C)alkanoylamino,(1-4C)alkanoyl, fluoro(1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-4C)alkyl,carbamoyl, N-alkyl or di-(N-alkyl)carbamoyl of up to 7 carbon atoms,sulphamoyl, N-alkyl or di-(N-alkyl)sulphamoyl of up to 6 carbon atoms,(1-4C)alkoxycarbonyl, (1-4C)alkanesulphonamido, (1-4C)alkyl.S(O)_(n)--[in which n is zero, 1 or 2] and 1H-tetrazol-5-yl; or B¹ is

(2) a 5 or 6-membered saturated or unsaturated heterocyclic ringoptionally bearing a (1-4C)alkyl group and containing a singleheteroatom selected from oxygen, sulphur and nitrogen or containing twoheteroatoms one of which is nitrogen and the other is oxygen, sulphur ornitrogen;

or T³ and T⁴ together form an (3-6C)alkenylene group, an (3-6C)alkylenegroup or an (3-6C)alkylene group in which a methylene is replaced bycarbonyl, provided that when T³ and T⁴ together form one of said latterthree groups then T² is additionally selected from any of the previousvalues defined for T⁴ ; Y is oxygen or a group of the formula --NRb--wherein Rb is hydrogen, (1-4C)alkyl, (1-4C)alkanoyl or benzoyl; linkinggroup A of formula IIc is selected from --CH═CH--, --CH═CH--CO--,--CO--CH═CH--, --CO--CH₂ --CH₂ --, --CH₂ --CH₂ --CO, --CH₂ -CO and--CO--CH₂ --; E¹ is hydrogen, (1-8C)alkyl or trifluoromethyl; E² ishydrogen, (1-8C)alkyl, halogeno, (1-4C)alkoxy, trifluoromethyl, carboxy,(1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl, cyano, nitro,(1-4C)alkanoyl, (1-4C)alkyl.S(O)_(m) -- [ in which m is zero, 1 or 2 ]or phenylsulphonyl; E³ is hydrogen, (1-8C)alkyl, (1-4C)alkoxy, halogenoor trifluoromethyl; E⁴ and E⁵ are optional substituents on linking groupA independently selected from (1-4C)alkyl, substituted (1-4C)alkylcontaining one or more fluoro substituents, phenyl, pyridyl, alkoxy,halogeno, cyano, nitro, carboxy, (1-4C)alkoxycarbonyl,(3-6C)alkenyloxycarbonyl, carbamoyl, N-alkylcarbamoyl anddi-(N-alkyl)carbamoyl of up to 7 carbon atoms, (1-4C)alkylthio,(1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylthio, phenylsulphinyl,phenylsulphonyl and (1-4C)alkanoyl; L¹ is (1-8C)alkyl; L² and L³ areindependently selected from hydrogen and (1-4C)alkyl; G¹ is selectedfrom hydrogen, (1-4C)alkyl optionally bearing one or more fluorosubstituents, halogeno, cyano, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl,carbamoyl and N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7carbon atoms; X is oxygen, sulphur or a group of the formula -NRcwherein Rc is hydrogen or (1-4C)alkyl; Ra is selected from hydrogen,(1-4C)alkyl, (1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; Zis 1H-tetrazol-5-yl, carboxy or a group of the formula CF₃ SO₂ NH--; andwherein any of said phenyl moieties of R¹, R², T¹, T², T³ or E.sup. 2may be unsubstituted or bear one or two substituents independentlyselected from (1-4C)alkyl, (1-4C)alkoxy, halogeno, cyano andtrifluoromethyl; or a non-toxic salt thereof.

It will appreciated that, depending on the nature of the substituents,certain of the formula I compounds may possess one or more chiralcentres and may be isolated in one or more racemic or optically activeforms. It is to be understood that this invention concerns any form ofsuch a compound of formula I which possesses the afore-mentioned usefulpharmacological properties, it being well known how to make opticallyactive forms, for example by synthesis from suitable chiralintermediates, and how to determine their pharmacological properties,for example by use of the standard tests described hereinafter.

It is to be understood that generic terms such as "alkyl" include bothstraight and branched chain variants when the carbon numbers permit.However, when a particular radical such as "propyl" is given, it isspecific to the straight chain variant, branched chain variants such as"isopropyl" being specifically named where intended. The same conventionapplies to other radicals.

A particular value for R¹, R², T¹ or T² where appropriate, include, byway of example, for alkyl: methyl, ethyl, propyl, butyl, isobutyl,sec-butyl, pentyl and hexyl; for cycloalkyl: cyclopropyl, cyclopentyland cyclohexyl; for alkyl containing one or more fluoro substituents:fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl andpentafluoroethyl; for alkyl bearing an (1-4C)alkoxy substituent:2-methoxyethyl and 2-ethoxyethyl; for cycloalkyl-alkyl:cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and2-cyclopentyl-ethyl; for phenylalkyl: benzyl, 1-phenylethyl and2-phenylethyl; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl; and for alkenyloxycarbonyl: allyloxycarbonyl,2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl.

A particular value for T³, T⁴, or for T² when it is selected from avalue for T⁴, where appropriate, includes, by way of example, for alkyl:methyl, ethyl and propyl; for alkoxycarbonyl: methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl; for alkenyloxycarbonyl:allyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl and3-methyl-3-butenyloxycarbonyl; for halogeno: fluoro, chloro, bromo andiodo; for alkoxy: methoxy, ethoxy and propoxy; for alkyl containing oneor more fluoro substituents: fluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl and pentafluoroethyl; for alkanoyl: formyl, acetyland butyryl; for N-alkylcarbamoyl: N-methyl and N-ethylcarbamoyl; fordi(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl;for alkylamino: methylamino, ethylamino and butylamino; and fordialkylamino: dimethylamino, diethylamino and dipropylamino.

A particular value for A¹ when it is alkylene is, for example,methylene, ethylene or propylene.

Particular values for R³, R⁴ or an optional substituent on B¹ when it isphenyl bearing one or two substituents, where appropriate, include, byway of example, for alkyl: methyl and ethyl; for alkoxy: methoxy andethoxy; for halogeno: chloro, bromo and iodo; for alkanoylamino:formamido, acetamido and propanamido; for alkanoyl: formyl, acetyl andbutyryl; for fluoroalkoxy: trifluoromethoxy, 2-fluoroethoxy,2,2,2-trifluoroethoxy and 3,3,3-trifluoropropoxy; for hydroxyalkyl:hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl; for alkoxyalkyl:2-methoxyethyl and 2-ethoxyethyl; for N-alkylcarbamoyl: N-methyl andN-ethylcarbamoyl; for di(N-alkyl)carbamoyl: N,N-dimethylcarbamoyl andN,N-diethylcarbamoyl; for N-alkylsulphamoyl: N-methyl andNethylsulphamoyl; for di(N-alkylsulphamoyl: N,N-dimethylsulphamoyl andN,N-diethylsulphamoyl; for alkoxycarbonyl: methoxycarbonyl,ethoxycarbonyl and propoxycarbonyl; for alkanesulphonamido:metanesulphonamido and ethanesulphonamido; for alkylthio: methylthio andethylthio; for alkylsulphinyl; methylsulphinyl and ethylsulphinyl; andfor alkylsulphonyl: methylsulphonyl and ethylsulphonyl.

A particular value for B¹ when it is a 5 or 6-membered saturated orunsaturated heterocyclic ring containing a single hetero atom selectedfrom oxygen, sulphur or nitrogen includes, for example, a thienyl,furyl, pyrrolyl, pyrrolidinyl, pyridyl and piperidyl ring.

A particular value for B¹ when it is a 5 or 6-membered saturated orunsaturated heterocyclic ring containing two heteroatoms one of which isnitrogen and the other is oxygen, sulphur or nitrogen includes, forexample, an imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl,thiazolyl, thiazolinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyrazinyl,pyridazinyl, piperazinyl, morpholinyl and thiomorpholinyl ring.

A particular value for an alkyl group which may be present on B¹ when itis a saturated or unsaturated heterocyclic ring is, for example, methylor ethyl.

A particular value for T³ and T⁴ when together they form (3-6C)alkyleneis, for example, trimethylene, tetramethylene or pentamethylene; whentogether they form (3-6C)alkenylene is, for example, 1-propenylene,2-propenylene, 1-butenylene, 2-butenylene or 3-butenylene; and whentogether they form (3-6C)alkylene wherein one of the methylene groups isreplaced by a carbonyl group is, for example, 1-oxopropylidene,3-oxopropylidene, 1-oxobutylidene or 4-oxobutylidene.

A particular value for Rb when it is alkyl is, for example, methyl orethyl; and when it is alkanoyl is, for example, formyl, acetyl orpropanoyl.

A particular value for E¹, E², E³ or L¹ when it is alkyl is, forexample, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl orhexyl.

A particular value for E² or E³ when it is halogeno is, for example,fluoro, chloro, bromo or iodo; and when it is alkoxy is, for example,methoxy, ethoxy or propoxy.

A particular value for E² when it is alkoxycarbonyl is, for example,methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl; when it isalkenyloxycarbonyl is, for example, allyloxycarbonyl,2-methyl-2-propenyloxycarbonyl or 3-methyl-3-butenyloxycarbonyl; when itis alkanoyl is, for example, formyl, acetyl or butyryl; when it isalkylthio is, for example, methylthio or ethylthio; when it isalkylsulphinyl is, for example, methylsulphinyl or ethylsulphinyl; andwhen it is alkylsulphonyl is, for example, methylsulphonyl orethylsulphonyl.

Particular values for E⁴ or E⁵ include, by way of example, for alkyl:methyl and ethyl; for alkyl containing one or more fluoro substituents:fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl andpentafluoroethyl; for alkoxy: methoxy and ethoxy; for halogeno: chloro,bromo and iodo; for alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl andpropoxycarbonyl; for alkenyloxycarbonyl: allyloxycarbonyl,2-methyl-2-propenyloxycarbonyl and 3-methyl-3-butenyloxycarbonyl; andfor alkonoyl: formyl, acetyl or butyryl; for N-alkylcarbamoyl:N-methylcarbamoyl and N-ethylcarbamoyl; for di-(N-alkyl)carbamoyl:N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl; for alkylthio:methylthio and ethylthio; for alkylsulphinyl: methylsulphinyl andethylsulphinyl; and for alkylsulphonyl: methylsulphonyl andethylsulphonyl.

A particular value for L², L³ or Rc when it is alkyl is, for example,methyl or ethyl.

A particular value for G¹ includes, by way of example, for alkyl:methyl, ethyl and propyl; for alkyl bearing one or more fluorosubstituents: fluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl orpentafluoroethyl; for halogeno: chloro, bromo and iodo; foralkoxycarbonyl: methoxycarbonyl and ethoxycarbonyl; for alkanoyl:formyl, acetyl or butyryl; for alkylcarbamoyl: N-methylcarbamoyl andN-ethylcarbamoyl; and for dialkylcarbamoyl: N,N-dimethylcarbamoyl orN,N-diethylcarbamoyl.

A particular value for Ra or for an optional substituent which may bepresent on a phenyl moiety of R¹, R², T¹, T², T³ or E² include, by wayof example, for alkyl: methyl and ethyl; for alkoxy: methoxy and ethoxy;and for halogeno: chloro, bromo and iodo.

A value for R¹, T¹ or T³ of particular interest is, for example, methyl,ethyl or propyl.

A value for R² of particular interest is, for example, hydrogen.

A value for T² of particular interest is, for example, hydrogen,alkoxycarbonyl or, when T³ and T⁴ form alkylene is, for example,halogeno.

A value for T⁴ of particular interest is, for example, alkoxycarbonyl orhalogeno.

A value of particular interest for T³ and T⁴ when together they formalkylene is, for example, trimethylene or tetramethylene.

A value for Y of particular interest is, for example, oxygen or a groupof the formula --NRb-- in which Rb is hydrogen.

A value for linking group A of formula IIc of particular interest is,for example, an optionally substituted group of the formula --CH═CH--,--CH═CH--CO-- or --CH₂ --CH₂ --CO--.

A value of particular interest for E¹ is, for example, methyl, ethyl orpropyl; for E² is, for example, hydrogen; for E³ is, for example,methyl, ethyl or halogeno; for E⁴ or E⁵ is, for example, hydrogen, alkyl(such as methyl or ethyl), halogeno, phenyl, pyridyl, alkoxycarbonyl,carbamoyl, N,N-dialkylcarbamoyl, cyano, hydroxy, phenylthio, orphenylsulphinyl.

A value of particular interest for L¹ is, for example, (1-4C)alkyl suchas ethyl, propyl or butyl; and for L² and L³ is, for example, methyl.

A value of particular interest for Q is, for example,2-(1-4C)alkylquinolin-4-yloxy (such as 2-methylquinolin-4-yloxy or2-ethylquinolin-4-yloxy),2-(1-4C)alkyl-5,6,7,8-tetrahydroquinolin-4-yloxy (such as2-methyl-5,6,7,8-tetrahydroquinolin-4-yloxy or2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy),2,6-di-(1-4C)alkyl-3-halogenopyrid-4-ylamino (such as2,6-dimethyl-3-chloropyrid-4-ylamino,2,6-dimethyl-3-iodopyrid-4-ylamino, 2,6-diethyl-3-chloropyrid-4-ylaminoor 2,6-diethyl-3-iodopyrid-4-ylamino),2,6-di-(1-4C)alkyl-4-halogeno-1H-pyrrolo[3,2-c]pyrid-1-yl (such as2,6-dimethyl-4-chloro-1H-pyrrolo[3,2-c]pyrid-1-yl),5,7-di-(1-4C)alkyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl (such as5,7-dimethyl-2-oxo-1,2-dihydro-2-oxo-1,6-naphthyridin-1-yl or5,7-diethyl-2-oxo-1,2-dihydro-2-oxo-1,6-naphthyridin-1-yl),5,7-di-(1-4C)alkyl-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl (suchas 5,7-dimethyl-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-1 -yl or5,7-diethyl-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl),2-(1-4C)alkyl-3H-imidazo[4,5-b]pyrid-3-yl (such as2-butyl-3H-imidazo[4,5-b]pyrid-3-yl) or2,5,7-tri-(1-4C)alkyl-3H-imidazo[4,5-b]-pyrid-3-yl (such as2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-yl. Of these values for Q,those which are embraced by partial structural formula IIb or IIc are ofspecial interest, especially those which are within sub-groups (c), (d)or (e) below.

A preferred value for G¹ is, for example, hydrogen or halogeno,especially bromo.

A preferred value for X is, for example, oxygen or a group of theformula NRc in which Rc is hydrogen, of which oxygen is particularlypreferred.

A preferred value for Ra is, for example, hydrogen.

A preferred value for Z is, for example, 1H-tetrazol-5-yl.

A combination of values of special interest is, for example, when R¹ andR³ are both alkyl; when T¹ and T³ are both alkyl; when T¹ is alkyl andT³ together with T⁴ form alkylene; or when E⁴ and E⁵ are both hydrogen.

A particular group of compounds of the formula I which are of interestcomprises compounds of the formula I as defined above but excludingthose compounds wherein one or both of E⁴ and E⁵ is selected fromphenyl, pyridyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoylof up to 7 carbon atoms, (1-4C)alkylthio, (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, phenylthio, phenylsulphinyl and phenylsulphonyl;or a non-toxic salt thereof.

Particular groups of compounds of the invention comprise those compoundsof the formula I in which Q constitutes:

(1) a group of the partial structural formula IIa in which ring B, R¹,R², R³ and R⁴ have any of the values defined hereinbefore;

(2) a group of the partial structural formula IIb in which T¹, T², T³,T⁴ and Y have any of the values defined hereinbefore;

(3) a group of the partial structural formula IIc in which E¹, E², E³,E⁴, E⁵ and linking group A have any of the values defined hereinbefore;and

(4) a group of the partial structural formula IId in which L¹, L² and L³have any of the values defined hereinbefore;

and wherein in each of said groups the variables G¹, X, Z and Ra haveany of the values defined hereinbefore; together with the non-toxicsalts thereof.

Sub-groups of compounds of the invention of special interest from withinthe groups of compounds of particular interest (1) to (4) above comprisethose compounds of the formula I in which Q constitutes:

(a) a group of the partial structural formula IIa wherein ring Btogether with the pyridine ring to which it is attached constitutes aquinoline ring;

(b) a group of the partial structural formula IIa wherein ring Btogether with the pyridine ring to which it is attached constitutes apyrido-pyridine ring (that is a naphthyridine);

(c) a group of the partial structural formula IIb wherein Y is an oxygenatom;

(d) a group of the partial structural formula IIb wherein Y is a groupof the formula --NH--;

(e) a group of the partial structural formula IIc wherein linking groupA together with the nitrogen atom and pyridine ring to which it isattached constitutes a 1,6-naphthyridin-2(1H)-one or a1,2,3,4-tetrahydronaphthyridin-2-one ring; and

(f) a group of the partial structural formula IIc wherein linking groupA together with the nitrogen atom and pyridine ring to which it isattached constitutes a 1H-pyrrolo[3,2-c]pyridine ring;

and wherein in each of said groups R¹, R², R³, R⁴, T¹, T², T³, T⁴, E¹,E², E³, E⁴ and E⁵, where present have any of the values defined aboveand the variables G¹, X, Z and Ra have any of the values definedhereinbefore; together with the non-toxic salts thereof.

Preferred compounds of the formula I from within those contained ingroups (1), (2), (3) or (4) or within sub-groups (a), (b), (c), (d), (e)or (f) above are those wherein the group Q--CH₂ -- is attached at the5-position of the ring. Of these, those compounds in which X is oxygenor a group of the formula --NRc wherein Rc is hydrogen or (1-4C)alkylare particularly preferred, and especially those compounds in which X is--NH-- or oxygen, particularly the latter.

Compounds of the invention which are of particular interest include, forexample, the specific embodiments set out hereinafter in theaccompanying Examples. Of these, the compounds of formula I described inExamples 8 and 9 are of special interest and these compounds, or anon-toxic salt thereof, are provided as a further feature of theinvention.

It will be appreciated that the formula I compounds can form salts withsuitable acids or bases. Particularly suitable non-toxic salts for suchcompounds include, for example, salts with bases affordingphysiologically acceptable cations, for example, alkali metal (such assodium and potassium), alkaline earth metal (such as magnesium andcalcium), aluminium and ammonium salts, as well as salts with suitableorganic bases, such as with ethanolamine, methylamine, diethylamine ortriethylamine, as well as salts with acids forming physiologicallyacceptable anions, such as salts with mineral acids, for example withhydrogen halides (such as hydrogen chloride and hydrogen bromide),sulphuric and phosphoric acid, and with strong organic acids, forexample with p-toluenesulphonic and methanesulphonic acids.

The compounds of formula I may be obtained by standard procedures oforganic chemistry well known in the art for the production ofstructurally analogous compounds. Such procedures are provided as afurther feature of the invention and include, by way of example, thefollowing procedures in which the generic radicals have any of thevalues given above, unless stated otherwise:

a) For those compounds in which Z is carboxy, a carboxylic acidderivative of the formula III, in which W is a protected carboxy groupselected from (1-6C)alkoxycarbonyl (especially methoxy-, ethoxy-,propoxy- or t-butoxy-carbonyl), phenoxycarbonyl, benzyloxycarbonyl andcarbamoyl, is converted to carboxy.

The conversion may be carried out, for example by hydrolysis,conveniently in the presence of a suitable base such as an alkali metalhydroxide, for example, lithium, sodium or potassium hydroxide. Thehydrolysis is generally carried out in the presence of a suitableaqueous solvent or diluent, for example in an aqueous (1-4C)alkanol,such as aqueous methanol or ethanol. However, it may also be performedin a mixture of an aqueous and non-aqueous solvent such as water andtoluene using a conventional quaternary ammonium phase transfercatalyst. The hydrolysis is generally performed at a temperature in therange, for example, 0°-120° C., depending on the reactivity of the groupW. In general, when W is carbamoyl, temperatures in the range, forexample, 40°-120° C. are required to effect the hydrolysis.

Alternatively, when W is benzyloxycarbonyl the conversion may also beperformed by hydrogenolysis, for example using hydrogen at 1-3 bar inthe presence of a suitable catalyst, such as palladium on charcoal or oncalcium sulphate, in a suitable solvent or diluent such as a(1-4C)alkanol (typically ethanol or 2-propanol) and at a temperature inthe range, for example, 0°-40° C.

Further, when W is t-butoxycarbonyl, the conversion may also be carriedout by hydrolysis at a temperature in the range, for example, 0°-100°C., in the presence of a strong acid catalyst, such as trifluoroaceticacid. The hydrolysis may either be performed in an excess of the acid orin the presence of a suitable diluent such as tetrahydrofuran, t-butylmethyl ether or 1,2-dimethoxyethane.

b) For those compounds of formula I wherein Z is tetrazolyl, a compoundof the formula IV in which P¹ is a suitable protecting group, such astrityl, benzhydryl, trialkyltin (for example trimethyltin ortributyltin) or triphenyltin, affixed to a nitrogen of the tetrazolylmoiety, is deprotected.

The reaction conditions used to carry out the deprotection necessarilydepend on the nature of the group P¹. As an illustration, when it istrityl, benzhydryl, trialkyltin or triphenyltin, the decompositionconditions include, for example, acid catalysed hydrolysis in a mineralacid (such as aqueous hydrochloric acid), conveniently in an aqueoussolvent (such as aqueous dioxan, methanol or 2-propanol). Alternatively,a trityl or benzhydryl group may be removed by hydrogenolysis, forexample as described in (a) above for conversion of a benzyloxycarbonylto a carboxy.

Compounds of the formula IV wherein P¹ is trialkyltin or triphenyltinmay be obtained, for example, by reaction of a nitrile of the formula IXwith a trialkyltin azide, such as tributyltin azide, or triphenyltinazide respectively. The reaction is conveniently carried out in asuitable solvent or diluent, such as toluene or xylene, and at atemperature in the range, for example, 50°-150° C. In a modifiedprocedure, a formula I compound wherein Z is tetrazolyl may be obtaineddirectly by in situ removal of the trialkyltin or triphenyltin groupwithout prior isolation of the formula III compound, for example, by theaddition of aqueous mineral acid or gaseous hydrogen chloride to thereaction mixture. Nitriles of the formula IX may be obtained, forexample, by alkylation of a compound of the formula Q.H with a nitrileof the formula X wherein Hal. stands for a suitable leaving group suchas chloro, bromo, iodo, methanesulphonyloxy or p-toluenesulphonyloxy,using similar conditions to those used in process (c) describedhereinafter. The necessary compounds of formula X may be made bystandard procedures such as those described in European PatentApplications (EPA), Publication Nos. 429257 and 430709, or by analogytherewith. Alternatively, the nitriles of the formula IX may be obtainedfrom stepwise conversion of a compound of formula I wherein Z is acarboxy group or a compound of the formula III under standardconditions. Additionally, a nitrile of the formula IX wherein Q is agroup of the partial structural formula IIb in which Y is the group--NRb-- and Rb is alkanoyl or benzoyl may be obtained from thecorresponding compound wherein Rb is hydrogen by acylation orbenzoylation under standard conditions.

It will be appreciated that procedures (a) and (b) may be carried outwith a compound of the formula III or IV respectively in which one ormore functional groups of Q and X are protected with suitable protectinggroups. For example, when X is an imino (--NH--) group it may beprotected with a suitable nitrogen protecting group such as an acylgroup (for example acetyl, trichloroacetyl or trifluoroacetyl) or analkyloxycarbonyl group (for example tert-butyloxycarbonyl). Theprotecting groups may be removed either during the carrying out ofprocedure (a) or (b), dependent on the conditions employed, orsubsequent thereto using conventional techniques. For example, atert-butyloxycarbonyl group used to protect X when it is imino may beremoved by base hydrolysis, using for example an alkali metal hydroxide(such as sodium hydroxide) in a suitable solvent (such as methanol orethanol) and at a temperature in the range of 0° to 100° C., preferably75° C. to ambient temperature.

c) A compound of the formula Q.H (or a tautomer thereof) is alkylatedwith a compound of the formula V wherein Hal. stands for a suitableleaving group such as chloro, bromo, iodo, methanesulphonyloxy orp-toluenesulphonyloxy.

The reaction is preferably carried out in the presence of a suitablebase, for example, an alkali metal alkoxide such as sodium or potassiummethoxide, ethoxide or tert-butoxide, an alkali metal hydride such assodium hydride, or an alkali metal carbonate such as sodium or potassiumcarbonate, or an organic base such as diisopropylethylamine or4-dimethylaminopyridine. The reaction is conveniently carried out in asuitable solvent or diluent, for example, a (1-4C)alkanol such asmethanol or ethanol, an ether such as tetrahydrofuran or dioxan, or apolar solvent such as N,N-dimethylformamide or N-methylpyrrolidone andat a temperature in the range, for example, 10°-100° C. In carrying outprocess (c), about two molecular equivalents of a suitable base isgenerally required.

It will be appreciated that it may be necessary to carry out procedure(c) with a starting material of formula V and/or Q.H in which one ormore functional groups present are protected with suitable protectinggroups. It will also be appreciated that procedure (c) is suitable forthe production of the starting materials of formula III for the reactiondescribed in (a) above if a compound of the formula Va is used in placeof a formula V compound. Similarly, using an analogous procedure, butstarting with the appropriate compound of the formula VI, the startingmaterials of the formula IV may be obtained for procedure (b). Thecompounds of formula V, Va and VI may be obtained as described in EPA,Publication Nos. 429257 and 430709 or by analogy therewith.

Many of the compounds of formula Q.H (or the tautomers thereof) arealready known and the remainder can be made by analogy therewith usingstandard procedures of organic chemistry well known in the art, forexample as described in standard works of heterocyclic chemistry such asthat edited by Elderfield. Certain 4-quinolones are described in EPA,Publication No. 412848 and certain 4-naphthyridones are described inInternational Patent Application No. PCT/GB90/01776. Certain 4-pyridonesare described in Monatshefte fur Chemie, 1969, 100, 132; J. Chem. Soc.(B), 1968, 866; Liebigs Ann. Chem., 1882, 1656; Heterocycles, 1982, 13,239; and J. Am. Chem. Soc., 1974, 96(4), 1152. Certain 4-aminopyridinesmay be obtained as described in Tet. Lett., 1990, 3485 fromintermediates obtainable as described in J. Het. Chem., 1989, 26, 1575or European Patent No. 129408. Certain imidazo[4,4-b]pyridines aredescribed in EPA 399731 and EPA 400974. Other compounds of the formulaQ.H may be obtained as illustrated in Schemes 1 to 10, or by analogytherewith.

d) For those compounds of formula I wherein Z is a group of the formulaCF₃ SO₂ NH--, a compound of the formula VII is reacted withtrifluoromethanesulphonic acid anhydride.

The reaction is preferably carried out in the presence of a base, suchas triethylamine, and conveniently in a suitable solvent or diluent, forexample dichloromethane, and at a temperature in the range of -78° C. toambient temperature. The compounds of the formula VII may be obtained byalkylation of a compound of formula Q.H with a compound of the formulaVIII (itself obtained using analogous procedures to those described inEPA 429257 and 430709) using similar conditions to those of process (c)above, followed by reduction of the nitro group in the intermediateobtained, for example by conventional catalytic hydrogenation.

Whereafter, those compounds of formula I wherein Z is 1H-tetrazol-5-ylmay be obtained by stepwise conversion of a compound of the formula Iwherein Z is a carboxy group, or a compound of the formula III, into thecorresponding nitrile under standard conditions, followed by reaction ofthe nitrile with an azide such as an alkali metal azide, preferably inthe presence of an ammonium halide, and preferably in the presence of asuitable polar solvent such as N,N-dimethylformamide and at atemperature in the range, for example, 50° to 160° C.

Whereafter, when a non-toxic salt of a compound of formula I isrequired, it may be obtained, for example, by reaction with theappropriate base affording a physiologically acceptable cation, or withthe appropriate acid affording a physiologically acceptable anion, or byany other conventional salt formation procedure.

Further, when an optically active form of a compound of formula I isrequired, one of the aforesaid proceses may be carried out using anoptically active starting material. Alternatively, the racemic form of acompound of formula I in which Z is an acidic group may be resolved, forexample by reaction with an optically active form of a suitable organicbase, for example, ephedrine, N,N,N-trimethyl-(1-phenylethyl)ammoniumhydroxide or 1-phenylethylamine, followed by conventional separation ofthe diastereoisomeric mixture of salts thus obtained, for example byfractional crystallisation from a suitable solvent, for example a (1-4C)alkanol, whereafter the optically active form of said compound offormula I may be liberated by treatment with acid using a conventionalprocedure, for example using an aqueous mineral acid such as dilutehydrochloric acid.

Certain of the intermediates defined herein are novel, for example thecompounds of the formula III, IV, IX and X, and are provided as afurther feature of the invention.

As stated above, the compounds of formula I will have beneficialpharmacological effects in warm-blooded animals (including man) indiseases and medical conditions where amelioration of thevasoconstrictor and fluid retaining properties of thereninangiotensin-aldosterone system is desirable, at least in part byantagonism of one or more of the physiological actions of AII. Thecompounds of the invention will thus be useful in the treatment ofdiseases or medical conditions such as hypertension, congestive heartfailure and/or hyperaldosteronism in warm-blooded animals (includingman), as well as in other diseases or medical conditions in which therenin-angiotensin-aldosterone system plays a significant causative role.The compounds of the invention may also be useful for the treatment ofocular hypertension, glaucoma, cognitive disorders (such as Alzheimer'sdisease, amnesia, senile dementia and learning disorders), as well asother diseases such as renal failure, cardiac insufficiency,post-myocardial infarction, cerebrovascular disorders, anxiety,depression and certain mental illnesses such as schizophrenia.

The antagonism of one or more of the physiological actions of AII and,in particular, the antagonism of the interaction of AII with thereceptors which mediate its effects on a target tissue, may be assessedusing one or more of the following, routine laboratory procedures:

Test A

This in vitro procedure involves the incubation of the test compoundinitially at a concentration of 100 micromolar (or less) in a bufferedmixture containing fixed concentrations of radiolabelled AII and a cellsurface membrane fraction prepared from a suitable angiotensin targettissue. In this test, the source of cell surface membranes is the guineapig adrenal gland which is well known to respond to AII. Interaction ofthe radiolabelled AII with its receptors (assessed as radiolabel boundto the particlate membrane fraction following removal of unboundradiolabel by a rapid filtration procedure such as is standard in suchstudies) is antagonized by compounds which also bind to the membranereceptor sites and the degree of antagonism (observed in the test asdisplacement of membrane-bound radioactivity) is determined readily bycomparing the receptor-bound radioactivity in the presence of the testcompound at the specified test concentration with a control valuedetermined in the absence of the test compound. Using this procedurecompounds showing at least 50% displacement of radiolabelled AII bindingat a concentration of 10⁻⁴ M are retested at lower concentrations todetermine their potency. For determination of the IC₅₀ (concentrationfor 50% displacement of radiolabelled AII binding), concentrations ofthe test compound are ordinarily chosen to allow testing over at leastfour orders of magnitude centred about the predicted approximate IC₅₀,which latter is subsequently determined from a plot of percentagedisplacement against concentration of the test compound.

In general, the compounds of formula I as defined above show significantinhibition in Test A at a concentration of about 50 micromolar or muchless.

Test B

This in vitro test involves the measurement of the antagonistic effectsof the test compound against AII-induced contractions of isolated rabbitaorta, maintained in a physiological salt solution at 37° C. In order toensure that the effect of the compound is specific to antagonism of AII,the effect of the test compound on noradrenaline-induced contractionsmay also be determined in the same preparation.

In general, the compounds of formula I as defined above show significantinhibition in Test B at a final concentration of about 50 micromolar ormuch less.

Test C

This in vivo test involves using terminally-anaesthetised or consciousrats in which an arterial catheter has been implanted under anaesthesiafor the measurement of changes in blood pressure. The AII antagonisticeffects of the test compound following oral or parenteraladministration, are assessed against angiotensin II-induced pressorresponses. To ensure that the effect is specific, the effect of the testcompound on vasopressin-induced pressor responses may also be determinedin the same preparation.

The compounds of formula I generally show specific AII-antagonistproperties in Test C at a dose of about 50 mg/kg body weight or muchless, without any overt toxicological or other untoward pharmacologicaleffect.

Test D

This in vivo test involves the stimulation of endogenous AIIbiosynthesis in a variety of species including rat, marmoset and dog byintroducing a diet of low sodium content and giving appropriate dailydoses of a saluretic known as frusemide. The test compound is thenadministered orally or parenterally to the animal in which an arterialcatheter has been implanted under anaesthesia for the measurement ofchanges in blood pressure.

In general compounds of formula I will show AII-antagonist properties inTest D as demonstrated by a significant reduction in blood pressure at adose of about 50 mg/kg body weight or much less, without any overttoxicological or other untoward pharmacological effect.

By way of illustration of the angiotensin II inhibitory properties ofcompounds of the formula I, the compound of Example 8 gave the followingresults in tests A and C described above:

In test A: an IC₅₀ of 3×10⁻⁸ M;

In test C: an ED₅₀ of 8.2 mg/kg (i.v. administration).

The compounds of formula I will generally be administered fortherapeutic or prophylactic purposes to warm-blooded animals (includingman) requiring such treatment in the form of a pharmaceuticalcomposition, as is well known in the pharmaceutical art. According to afurther feature of the invention there is provided a pharmaceuticalcomposition comprising a compound of formula I, or a salt thereof, asdefined above, together with a pharmaceutically acceptable diluent orcarrier. Such compositions will conveniently be in a form suitable fororal administration (e.g. as a tablet, capsule, solution, suspension oremulsion) or parenteral administration (e.g. as an injectable aqueous oroily solution, or injectable emulsion).

The compounds of formula I may also be advantageously administered fortherapeutic or prophylactic purposes together with anotherpharmacological agent known in the general art to be of value intreating one or more of the diseases or medical conditions referred tohereinabove, such as a beta-adrenergic blocker (for example atenolol), acalcium channel blocker (for example nifedipine), an angiotensinconverting enzyme (ACE) inhibitor (for example lisinopril) or a diuretic(for example furosemide or hydrochlorothiazide). It is to be understoodthat such a combination therapy constitutes a further aspect of theinvention.

In general a compound of formula I (or a pharmaceutically acceptablesalt thereof as appropriate) will generally be administered to man sothat, for example, a daily oral dose of up to 50 mg/kg body weight (andpreferably of up to 10 mg/kg) or a daily parenteral dose of up to 5mg/kg body weight (and preferably of up to 1 mg/kg) is received, givenin divided doses as necessary, the precise amount of compound (or salt)administered and the route and form of administration depending on size,age and sex of the person being treated and on the particular disease ormedical condition being treated according to principles well known inthe medical arts.

In addition to their aforesaid use in therapeutic medicine in humans,the compounds of formula I are also useful in the veterinary treatmentof similar conditions affecting commercially valuable warm-bloodedanimals, such as dogs, cats, horses and cattle. In general for suchtreatment, the compounds of the formula I will generally be administeredin an analogous amount and manner to those described above foradministration to humans. The compounds of formula I are also of valueas pharmacological tools in the development and standardisation of testsystems for the evaluation of the effects of AII in laboratory animalssuch as cats, dogs, rabbits, monkeys, rats and mice, as part of thecontinuing search for new and improved therapeutic agents.

The invention will now be illustrated by the following non-limitingExamples in which, unless otherwise stated

(i) concentrations and evaporations may be carried out by rotaryevaporation in vacuo;

(ii) operations are carried out at room temperature, that is in therange 18°-26° C.;

(iii) flash column chromatography is performed on Merck Kieselgel 60(Art. no. 9385) obtained from E Merck, Darmstadt, Germany;

(iv) yields, where given, are intended for the assistance of the readeronly and are not necessarily the maximum attainable by diligent processdevelopment;

(v) ¹ H NMR spectra were determined at 200 MHz in CDCl₃ or d₆-dimethylsulphoxide using tetramethylsilane (TMS) as an internalstandard, and are expressed as chemical shifts (delta values) in partsper million relative to TMS using conventional abbreviations fordesignation of major peaks: s, singlet; m, multiplet; t, triplet; br,broad; d, doublet; and

(vi) the term "1H-tetrazol-5-yl" stands for "1H-1,2,3,4-tetrazol-5-yl".

EXAMPLE 1

1,1-Dimethylethyl3-bromo-5-[[2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy]methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indole-1-carboxylate(A) (100 mg) in a mixture of ethanol (15 ml) and 2M aqueous sodiumhydroxide solution (5 ml) is heated at 60° C. for 3 hours. The mixtureis cooled and acidified with 2M hydrochloric acid to pH 5 to 6. Themixture is then extracted with dichloromethane and the combined extractsare dried (MgSO₄) and evaporated to give3-bromo-5-[[2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy]methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indole.

The starting material A may be obtained as follows:

(i) Sodium hydride (60% dispersion in oil; 0.206 g) is added to astirred solution of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone (0.9 g)[itelf obtained as a solid (m.p. 226°-227° C.) using an analogousprocedure to that described in Liebigs. Ann. Chem., 1982, 1656-1658 forthe preparation of 2-methyl-5,6,7,8-tetrahydro-4(1H)-quinolone butstarting from 2-ethyl-4(1H)-quinolone] in N,N-dimethylformamide (DMF)(25 ml). The mixture is stirred at 50° C. until evolution of hydrogenceases and then 1,1-dimethylethyl3-bromo-5-(bromomethyl)-2-[2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]phenyl]-1H-indole-1-carboxylate(3.87 g) [obtained as described in European Patent Application,Publication No. 429257] is added. The solution is stirred at 50° C. for30 minutes and then at ambient temperature for 72 hours. The solvent isremoved by evaporation and the residue partitioned between ethyl acetate(50 ml) and water (50 ml). The organic layer is separated, washed withsaturated sodium chloride solution (30 ml) and dried (MgSO₄). Thesolvent is removed by evaporation and the residue purified by flashchromatography, eluting with ethyl acetate/hexane (1:1 v/v with gradualincrease in the proportion of ethyl acetate) to give 1,1-dimethylethyl3-bromo-5-[[2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy]methyl]-2-[2-[2-[2-(triphenylmethyl)-2H-tetrazol-5-yl)phenyl]-1H-indole-1-carboxylate(B).

(ii) 6M Hydrochloric acid (2 ml) is added to a mixture of compound B(0.16 g) in methanol (20 ml) and the mixture is stirred for 16 hours.The mixture is adjusted to pH 5 to 6 with 2M sodium hydroxide solution,water (20 ml) is added and the mixture extracted with dichloromethane(3×20 ml). The combined extracts are dried (MgSO₄) and evaporated togive 1,1-dimethylethyl3-bromo-5-[[2-ethyl-5,6,7,8-tetrahydroquinolin-4-yloxy]methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indole-1-carboxylate(A).

EXAMPLES 2-7

Using an analogous procedure to that described in Example 1, butstarting from the appropriate compound of formula Q.H in part (i) inplace of 2-ethyl-5,6,7,8-tetrahydro-4(1H)-quinolone, the followingcompounds of formula I may be obtained:

(Example 2):3-bromo-5-[[2-ethylquinolin-4-yloxy]methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indole,starting from 2-ethyl-4(1H)-quinolone, itself obtained as described inEPA 412848.

(Example 3):3-bromo-5-[[2,6-diethyl-3-iodopyrid-4-ylamino]methyl]-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indole,starting from 4-amino-2,6-diethyl-3-iodopyridine, itself obtained asfollows:

(i) Methyl 4-amino-2,6-diethylpyridine-3-carboxylate (3.94 g), itselfobtained using an analogous procedure to that described in Tet. Lett.,1990, 3485 but starting from 3-amino-2-pentenenitrile (obtained asdescribed in J. Het. Chem., 1989, 26, 1575) and methyl propionylacetate,is added to a mixture of 2M sodium hydroxide solution (9.5 ml) andmethanol (40 ml) and the mixture is heated at reflux for 16 hours. Thesolution is cooled to ambient temperature and volatile material isremoved by evaporation. The residue is partitioned between ethyl acetateand a mixture of 2M hydrochloric acid (9.5 ml) and water (20 ml). Theaqueous phase is separated, water is removed by evaporation and theresidue is extracted with ethyl acetate/methanol (1:1 v/v). The combinedorganic extracts are filtered and solvent is removed from the filtrateby evaporation to give 4-amino-2,6-diethylpyridine-3-carboxylic acid(3.46 g) as a yellow-brown foam; NMR (d₆ -DMSO): 1.18(m,6H), 2.64(q,2H),3.12 (q,2H), 6.49(s,1H), 8.28(broad s,2H),; mass spectrum (chemicalionisation, ammonia): 195(M+H)⁺.

(ii) 4-Amino-2,6-diethylpyridine-3-carboxylic acid (3.26 g) is heated at220° C. for 50 minutes. The residue is cooled to ambient temperature andpurified by flash chromatography eluting with concentrated aqueousammonia solution/dichloromethane/methanol (1:85:15 v/v) to give4-amino-2,6-diethylpyridine (1.94 g) as a solid, m.p. 133°-137° C.; NMR(CDCl₃ /d₆ -DMSO): 1.24(t,6H), 2.68(q,4H), 4.48(broad s,2H), 6.27(s,2H);mass spectrum (chemical ionisation, ammonia): 151(M+H)⁺.

(iii) 4-Amino-2,6-diethylpyridine (1.8 g) is added to a solution ofiodine (3.1 g) and [bis(trifluoroacetoxy)iodo]benzene (5.7 g) in amixture of dichloromethane (70 ml) and methanol (20 ml) and the mixtureis stirred for 16 hours. Solvent is removed by evaporation and theresidue is partitioned between ethyl acetate and a mixture of saturatedsodium metabisulphite solution (50 ml) and saturated sodium carbonatesolution (150 ml). The organic phase is separated, washed with saturatedsodium chloride solution and dried. Solvent is removed by evaporationand the residue is purified by flash chromatography eluting withdichloromethane/methanol (97:3 v/v) to give4-amino-2,6-diethyl-3-iodopyridine (1.33 g) as a solid, m.p. 72°-74° C.;NMR (CDCl₃): 1.25(m,6H), 2.65(q,2H), 2.96(q,2H), 4.59(broad s,2H),6.30(s,1H); mass spectrum (chemical ionisation, ammonia): 277(M+H)⁺.

(Example 4):1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indol-5-yl]methyl]-4-chloro-2,6-dimethyl-1H-pyrrolo[3,2-c]pyridine,starting from 4-chloro-2,6-dimethyl-1H-pyrrolo[3,2-c]pyridine (itselfobtained using the method described in Tetrahedron, 1976, 32,1383-1390).

(Example 5):1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indol-5yl]methyl]-5,7-dimethyl-1,6-naphthyrid-2(1H)-one,starting from 5,7-dimethyl-1,6-naphthyrid-2(1H)-one (itself obtained asdescribed in Chem. Pharm. Bull. 1985, 33, 4764).

(Example 6):3-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indol-5yl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine,starting from 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (itselfobtained as described in European Patent Application, publication No.400974).

(Example 7):3-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-1H-indol-5-yl]methyl]-2-butyl-3H-imidazo[4,5-b]pyridine,starting from 2-butyl-3H-imidazo[4,5-b]pyridine (itself obtained asdescribed in Indian J. Chem., Sec. B. 1978, 16B, 531).

EXAMPLE 8

Concentrated hydrochloric acid (1 ml) was added to a suspension of4-[(3-bromo-2-(2-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinoline(A) (650 mg) in methanol (2 ml) and ethanol (4 ml). The mixture waswarmed gently until the solid dissolved and then left to stand for 2hours. The precipitated solid was filtered off, slurried with ether (10ml) and recrystallised from methanol to give4-[(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methoxy]-2-ethyl-5,6,7,8-tetrahydroquinolinehydrochloride, m.p. 210°-212° C.; NMR (d₆ -DMSO): 1.3(t, 3H),1.65-1.9(m, 4H), 2.5-2.7(m, 2H), 2.9-3.1(m, 4H), 5.6(s, 2H), 7.55(s,1H), 7.6(s, 2H), 7.7(s, 1H), 7.75-7.85(m, 2H), 7.9-8.0(m, H); massspectrum (+ve fast atom bombardment (+FAB), DMSO/Methanol/nitrobenzylalcohol(NBA)): 532 (M+H)⁺ ; microanalysis, found: C, 57.0; H, 4.6; N,12.4%; C₂₇ H₂₄ BrN₅ O₂.HCl requires: C, 57.2; H, 4.45; N, 12.4%.

The starting material (A) was obtained as a foam in 51% yield using ananalogous procedure to that described in Example 1, part (i), butstarting from5-[2-(3-bromo-5-(bromomethyl)-benzofuran-2-yl)phenyl]-triphenylmethyl-2H-tetrazole(obtained as described in European Patent Application, Publication No.434249); NMR: 1.3(t, 3H), 1.7-1.95(m, 4H), 2.7(t, 2H), 2.75(q, 2H),2.9(t, 2H), 5.2(s, 2H), 6.6(s, 1H), 6.8-6.9(m, 6H), 7.05-7.4(m, 11H),7.45-7.8(m, 4H), 8.2(dd, 1H).

EXAMPLE 9

Using an analogous procedure to that described in Example 8, butstarting from1-[(3-bromo-2-(2-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methyl]-5,7-diethyl-1,6-naphthyridin-2(1H)-one(A), there was obtained in 33% yield1-[(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methyl]-5,7-diethyl-1,6-naphthyridin-2(1H)-onehydrochloride, m.p. 214°-216° C.; NMR (d₆ -DMSO): 1.25-1.35(2×t, 6H),3.0(q, 2H), 3.3(q, 2H), 5.7(s, 2H), 7.0(d, 1H), 7.4(d, 1H), 7.5(d, 1H),7.6(s, 1H), 7.7-8.0 (m, 5H), 8.4(d, 1H); mass spectrum (+ve FAB,methanol/NBA): 555 (M+H)⁺ ; microanalysis, found: C, 56.3; H, 4.4; N,13.7; H₂ O, 1.2%; C₂₈ H₂₃ BrN₆ O₂.HCl.0.5H₂ O.0.1.Et₂ O requires: C,56.1; H, 4.3; N, 13.8; H₂ O, 1.5%.

The starting material A was obtained as follows:

(i) Palladium (II) acetate (50 mg) and tri(2-methylphenyl)-phosphine (50mg) were added to a solution of 4-amino-2,6-diethyl-3-iodopyridine (1.3g), ethyl acrylate (1.2 ml) and triethylamine (1.2 ml) in DMF (25 ml).The mixture was heated at 130° C. for 2 hours and then allowed to cool.Volatile material was removed by evaporation and the residue waspurified by flash chromatography, eluting with aqueous ammonia (density0.88 g/ml)/dichloromethane/methanol (1:200:20, v/v/v) to giveethyl-3-[(4-amino-2,6-diethyl)pyridin-3-yl]acrylate as an oil; NMR(CDCl₃): 1.15-1.45(m, 9H), 2.7(g, 2H), 2.8(q, 2H), 4.25(q, 2H),4.5(broad s, 2H), 6.25(d, 2H), 7.75(d, 2H); mass spectrum (chemicalionisation, ammonia): 249 (M+H)⁺.

(ii) A solution of ethyl-3-[(4-amino-2,6-diethyl)pyridin-3-yl]acrylate(600 mg) in dry methanol (10 ml) was added to a solution of sodiummethoxide, prepared from sodium (500 mg) and dry methanol (30 ml), andthe mixture was heated at reflux under an atmosphere of argon for 3hours. Solvent was removed by evaporation and the residue partitionedbetween ethyl acetate and water. The aqueous phase was separated andextracted with ethyl acetate. The combined organic solutions were washedwith saturated sodium chloride solution and then dried (MgSO₄). Thesolvent was removed by evaporation and the residue was triturated withether to give 5,7-diethyl-1,6-naphthyridin-2(1H)-one (310 mg), as asolid, m.p. 170°-171° C.; NMR (CDCl₃): 1.45(m, 6H), 2.85(q, 2H), 3.1(q,2H), 6.7(d, 1H), 6.95(s, 1H), 8.05(d, 1H), 12.05(broad s, 1H): massspectrum (chemical ionisation, ammonia): 203(M+H)⁺.

(iii) A mixture of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (291 mg),5-[2-(3-bromo-5-(bromomethyl)benzofuran-2-yl)phenyl]-2-triphenylmethyl-2H-tetrazole(1.30 g), potassium t-butoxide (168 mg) and1,4,7,10,13,16-hexaoxacyclooctadecane (40 mg) in dry tetrahydrofuran (15ml) was stirred under an atmosphere of argon for 18 hours. Saturatedsodium chloride solution (25 ml) was added and the mixture was extractedwith ether (2×25 ml). The extracts were dried (MgSO₄) and concentratedby evaporation. The residue was purified by flash chromatography,eluting with ethyl acetate/hexane (3:1 v/v), to give1-[(3-bromo-2-(2-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methyl]-5,7-diethyl-1,6-naphthyridin-2(1H)-one(A) (640 mg) as a foam; NMR: 1.2(t, 3H), 1.35(t, 3H), 2.7(q, 2H), 3.1(q,2H), 5.6(s, 2H), 6.8-7.25(m, 19 H), 7.35(s, 1H), 7.5-7.7(m, 3H), 8.0(d,1H), 8.2(d, 1H).

EXAMPLE 10

Using an analogous procedure to that described in Example 8, butstarting from1-[(3-bromo-2-(2-(2-triphenylmethyl-2H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methyl]-5,7-diethyl-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one(A), there may be obtained1-[(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methyl]-5,7-diethyl-1,2,3,4-tetrahydro-1,6-naphthyridin-2-onehydrochloride.

The starting material A may be obtained using an analogous procedure tothat described in Example 9, part (iii), but starting from5,7-diethyl-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one, itself obtainedas follows:

A solution of ethyl-3-[(4-amino-2,6-diethyl)pyridin-3-yl]-acrylate (540mg) in ethanol (30 ml) was catalytically hydrogenated over 30% palladiumon carbon. When uptake of hydrogen ceased the catalyst was removed byfiltration through diatomaceous earth. The filtrate was concentrated byevaporation and the residue was purified by flash chromatography,eluting with dichloromethane/methanol (9:1 v/v), to give5,7-diethyl-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one (380 mg), as asolid, m.p. 100° C.; NMR (CDCl₃): 1.15-1.4(m,6H), 2.6-2.9(m,6H),2.95(t,2H), 6.45(s,1H), 8.5(broad s,1H); mass spectrum (chemicalionisation, ammonia): 205(M+H)⁺.

EXAMPLES 11-15

Using an analogous procedure to that described in Example 8, butstarting from the appropriate compound of formula IV, which itself maybe obtained using an analogous procedure to that described in Example 1,part (i) or Example 9, part (iii) but starting from the appropriatecompound of formula Q.H indicated and5-[2-(3-bromo-5-(bromomethyl)benzofuran-2-yl)phenyl]-2-triphenylmethyl-2H-tetrazole,the following compounds of formula I may be obtained:

(Example 11):4-[(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methoxy]2-ethylquinolinehydrochloride, starting from Q.H=2-ethyl-4(1H)-quinolone, itselfobtained as described in EPA 412848.

(Example 12):4-[(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methylamino]-2,6-diethyl-3-iodopyridinehydrochloride, starting from Q.H=4-amino-2,6-diethylpyridine.

(Example 13):1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-benzofuran-5-yl]methyl]-4-chloro-2,6-dimethyl-1H-pyrrolo[3,2-c]pyridinehydrochloride, starting fromQ.H=4-chloro-2,6-dimethyl-1H-pyrrolo[3,2-c]pyridine.

(Example 14):3-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-benzofuran-5-yl]methyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridinehydrochloride, starting fromQ.H=5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine.

(Example 15):3-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-benzofuran-5-yl]methyl]-2-butyl-3H-imidazo[4,5-b]pyridinehydrochloride, starting from Q.H=2-butyl-3H-imidazo[4,5-b]pyridine.

EXAMPLE 16

(Note: all parts by weight)

The compounds of the invention may be administered for therapeutic orprophylactic use to warm-blooded animals such as man in the form ofconventional pharmaceutical compositions, typical examples

    ______________________________________                                        a) Capsule (for oral administration)                                          Active ingredient *      20                                                   Lactose powder           578.5                                                Magnesium stearate       1.5                                                  b) Tablet (for oral administration)                                           Active ingredient *      50                                                   Microcrystalline cellulose                                                                             400                                                  Starch (regelatinised)   47.5                                                 Magnesium stearate       2.5                                                  c) Injectable Solution                                                        (for intravenous administration)                                              Active ingredient *      0.05-1.0                                             Propylene glycol         5.0                                                  Polyethylene glycol (300)                                                                              3.0-5.0                                              Purified water           to 100%                                              d) Injectable Suspension                                                      (for Intramuscular administration)                                            Active ingredient *      0.05-1.0                                             Methylcellulose          0.5                                                  Tween 80                 0.05                                                 Benzyl alcohol           0.9                                                  Benzalkonium chloride    0.1                                                  Purified water           to 100%                                              ______________________________________                                    

Note: the active ingredient * may typically be an Example describedhereinbefore and will conveniently be present as a pharmaceuticallyacceptable acid-addition salt, such as the hydrochloride salt. Tabletsand capsules formulations may be coated in conventional manner in orderto modify or sustain dissolution of the active ingredient. Thus, forexample, they may be coated with a conventional enterically digestiblecoating. ##STR1##

What we claim is:
 1. A heterocyclic compound of the formula Iwherein Qis a group of the partial structural formula IIc, ##STR2## in whichlinking group A of formula IIc is selected from --CH═CH--,--CH═CH--CO--, --CO--CH═CH--, --CO--CH₂ --CH₂ --, --CH₂ --CH₂ --CO,--CH₂ --CO and --CO--CH₂ ; E¹ is hydrogen, (1-8C)alkyl ortrifluoromethyl; E² is hydrogen, (1-8C)alkyl, halogeno, (1-4C)alkoxy,trifluoromethyl, carboxy, (1-4C)alkoxycarbonyl,(3-6C)alkenyloxycarbonyl, cyano, nitro, (1-4C)alkanoyl,(1-4C)alkyl.S(O)_(m) --(in which m is zero, 1 or 2) or phenylsulphonyl;E³ is hydrogen, (1-8C)alkyl, (1-4C)alkoxy, halogeno or trifluoromethyl;E⁴ and E⁵ are optional substituents on linking group A independentlyselected from (1-4C)alkyl, substituted (1-4C)alkyl having one or morefluoro substituents, phenyl, pyridyl, alkoxy, halogeno, cyano, nitro,carboxy, (1-4C)alkoxycarbonyl, (3-6C)alkenyloxycarbonyl; carbamoyl,N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbon atoms,(1-4C)alkylthio, (1-4C)alkylsulphinyl, (1-4C)alkylsulphonyl, phenylthio,phenylsulphinyl, phenylsulphonyl and (1-4c)alkanoyl; G¹ is selected fromhydrogen, (1-4C)alkyl optionally bearing one or more fluorosubstituents, halogeno, cyano, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl,carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to 7 carbonatoms; X is oxygen, sulphur or a group of the formula --NRc wherein Rcis hydrogen or (1-4C)alkyl; Ra is selected from hydrogen, (1-4C)alkyl,(1-4C)alkoxy, halogeno, trifluoromethyl, cyano and nitro; Z is1H-tetrazol-5-yl, carboxy or a group of the formula CF₃ SO₂ NH--; andwherein any of said phenyl moieties of E² may be substituted or bear oneor two substituents independently selected from (1-4C)alkyl,(1-4C)alkoxy, halogeno, cyano and trifluoromethyl; or a non-toxic saltthereof.
 2. A compound as claimed in claim 1 but excluding thosecompounds wherein one or both of E⁴ and E⁵ is selected from phenyl,pyridyl, carbamoyl, N-alkylcarbamoyl and di-(N-alkyl)carbamoyl of up to7 carbon atoms, (1-4C)alkylthio, (1-4C)alkylsulphinyl,(1-4C)alkylsulphonyl, phenylthio, phenylsulphinyl and phenylsulphonyl;or a non-toxic salt thereof.
 3. A compound as claimed in claim 1whereinE¹ is hydrogen, methyl, ethyl, propyl, butyl, isobutyl,sec-butyl, pentyl, hexyl or trifluoromethyl; E² is hydrogen, methyl,ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, fluoro,chloro, bromo, iodo, methoxy, ethoxy, propoxy, trifluoromethyl, carboxy,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl, cyano,nitro, formyl, acetyl, butyryl, methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, methylsulphonyl, ethylsulphonyl or phenylsulphonyl; E³is hydrogen, methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, pentyl,hexyl, fluoro, chloro, bromo, iodo, methoxy, ethyoxy, propoxy ortrifluoromethyl; E⁴ and E⁵ are optional substituents on linking group Aindependently selected from methyl, ethyl, fluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, phenyl,pyridyl, methoxy, ethoxy, chloro, bromo, iodo, cyano, nitro, carboxy,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, allyloxycarbonyl,2-methyl-2-propenyloxycarbonyl, 3-methyl-3-butenyloxycarbonyl,carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, methylthio, ethylthio, methylsulphinyl,ethylsulphinyl, methylsulphonyl, ethylsulphonyl or phenylthio,phenylsulphinyl; phenylsulphonyl, formyl, acetyl and butyryl; G¹ isselected from hydrogen, methyl, ethyl, propyl, fluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, chloro, bromo,iodo, cyano, methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, butyryl,carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl,and N,N-diethylcarbamoyl; X is oxygen, sulphur or a group of the formula-NRc wherein Rc is hydrogen, methyl or ethyl; Ra is selected fromhydrogen, methyl, ethyl, methoxy, ethoxy, chloro, bromo, iodo,trifluoromethyl, cyano and nitro; and wherein any of said phenylmoieties of E² may be unsubstituted or bear one or two substituentsindependently selected from methyl, ethyl, methoxy, ethoxy, chloro,bromo, iodo, cyano and trifluoromethyl; or a non-toxic salt thereof. 4.A compound of formula I as claimed in claim 1, wherein Q is selectedfrom2,6-di-(1-4C)alkyl-4-halogeno-1H-pyrrolo(3,2-c)pyrid-1-yl,5,7-di-(1-4C)alkyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl, and5,7-di-(1-4C)alkyl-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl.
 5. Acompound of the formula I as claimed in claim 1 or claim 4 wherein X isoxygen.
 6. A compound of the formula I which is1-(3-bromo-2-(2-(1H-tetrazol-5-yl)phenyl)benzofuran-5-yl)methyl)-5,7-diethyl-1,6-naphthyridin-2(1H)-one;or a non-toxic salt thereof.
 7. A salt as claimed in claim 1 which isselected from salts with acids forming physiologically acceptable anionsand salts with bases forming physiologically acceptable cations.
 8. Apharmaceutical composition which comprises a compound of the formula I,or a non-toxic salt thereof, as claimed in claim 1, together with apharmaceutically acceptable diluent or carrier.
 9. A method forantagonising one or more of the actions of angiotensin II in awarm-blooded animal requiring such treatment which comprisesadministering to said animal an antagonistically effective amount of acompound of formula I, or a non-toxic salt thereof, as defined in claim1.